The main products of cyclophosphamide bioactivation exert a cardiotoxic effect at clinical important concentrations in AC16 cardiac cells

Cyclophosphamide is used against lymphomas, solid tumors, namely breast, ovarian, bone and soft tissue tumors, in bone marrow transplant conditioning regimens and also in the treatment of autoimmune diseases. Despite its broad use, the application of cyclophosphamide is dose limited by its cardiotoxic effects, which have been linked to its intricate bioactivation process. In this study, we evaluated the cytotoxicity of cyclophosphamide (100 to 10000 μM) and two of its main metabolites, 4-hydroxycyclophosphamide (1 to 25 μM) and acrolein (5 to 100 μM) in AC16 cells, a human cardiomyocyte cell line. Furthermore, metabolomic evaluation was conducted in proliferative and differentiated cells after their incubation for 24h with subtoxic concentrations LC05 of cyclophosphamide, 4-hydroxycyclophosphamide and acrolein.